The present invention relates to esters of estradiol which exhibit potent oral and parenteral estrogenic activity. The invention provides pharmaceutical compositions comprising the compounds and methods for their use.
The utility of estrogenic substances in the practice of medicine is well documented. Estrogens may be used for the replacement of the natural hormone, estradiol, in hypogonadism and following removal of the ovaries or cessation of ovarian activity during menopause. They are also widely employed as a component of oral contraceptives. The natural hormones, estradiol and estrone are only weakly active upon oral administration and, therefore, relatively large dosages must be employed. The most frequently used oral preparations, 17.alpha.-ethynylestradiol and its 3-methyl ether, are synthetic derivatives of the natural hormone. Oral activity appears to be due to the presence of the 17-ethynyl group which protects the molecule from degradation by the liver following absorption from the gut and passage into the hepatoportal system (so-called "first pass effect").
While the advantages of estradiol and ethynylestradiol are substantial, as evidenced by their wide commercial adoption, these products are not without their drawbacks. These "ethynylated" estrogens have been associated with a number of side effects some of which are serious in nature (Smith, R. L., In: Briggs, M. H. and Diczfalusy, E. (Eds.): Pharmaceutical Models in Contraceptive Development Copenhagen, Bogtrykkeriet Forum, 1974). These problems are extremely serious when viewed in terms of the large number of women who take preparations such as those listed above on a long and regular basis. These problems include enhancing the risk of endometrial carcinoma; induction of malignant carcinoma especially in the cervix, breast, vagina and liver; promotion of gallbladder disease, thromboembolic and thrombotic diseases, myocardial infarction, hepatic adenoma, elevated blood pressure, and hypercalcemia; and a worsening of glucose tolerance. These problems tend to manifest themselves at the dosage levels needed to achieve the desired primary estrogenic and contraceptive effects. Many of these side effects are considered to be dose-related. If more potent oral estrogens were available, particularly those lacking the ethynyl group, they could be used in lower doses and the side effects could, at least in part, be reduced or eliminated.
Accordingly, it is desirable to have orally active estrogens lacking the ethynyl group which are clinically superior to those currently available. It is also desirable to have potent parenterally active estrogens in those circumstances where medical prudence favors administration by such routes. The present invention addresses these and other needs.